A three-component reaction for diversity-oriented synthesis of polysubstituted piperidines: Solution and solid-phase optimization of the first tandem aza [4+2]/allylboration

Article abstract of DOI:10.1002/chem.200390049

This article describes the design and optimization of a simple three-component aza[4+2]/allylboration reaction to access polysubstituted α-hydroxyalkyl piperidines in a highly diastereo-controlled fashion from maleimides, 4- boronohydrazonodienes, and ald

Full text of DOI:10.1002/chem.200390049

FULL PAPER
A Three-Component Reaction for Diversity-Oriented Synthesis of
Polysubstituted Piperidines: Solution and Solid-Phase Optimization of the
First Tandem Aza[4‡2]/Allylboration
Barry B. Toure¬,[a] Hamid R. Hoveyda,[a, b] Jyoti Tailor,[a] Agnieszka Ulaczyk-Lesanko,[a]
and Dennis G. Hall*[a]
Abstract: This article describes the de-
sign and optimization of a simple three-
component aza[4‡2]/allylboration reac-
tion to access polysubstituted a-hydroxy-
alkyl piperidines in a highly diastereo-
controlled fashion from maleimides, 4-
boronohydrazonodienes, and aldehydes.
The aldehyde component does not in-
terfere with the first aza[4‡2] step, and
it was found that this tandem reaction
provides better yields of piperidine
products 5 when carried out in one-pot.
The required 4-borono-hydrazono-
dienes 1 are synthesized efficiently from
the condensation of 3-boronoacrolein
pinacol ester (4) with hydrazines. Over-
all, the three-component process using
N-substituted maleimides as dienophiles
produces four stereogenic centers and is
quite general. It tolerates the use of a
wide variety of aldehydes and hydrazine
precursors with different electronic and
steric characteristics. By allowing such a
wide substrate scope and up to four
elements of diversity, this reaction proc-
ess is particularly well adapted towards
applications in diversity-oriented syn-
thesis of polysubstituted piperidine de-
rivatives. The suitability of the aza[4‡2]/
allylboration reaction for use in solid-
phase chemistry was also demonstrated
using a N-arylmaleidobenzoic acid func-
tionalized resin. This novel multicompo-
nent reaction thus offers a high level of
stereocontrol and versatility in the prep-
aration of densely functionalized nitro-
gen heterocycles.
Keywords:
boron
¥
diastereo-
selectivity ¥ heterocycles ¥ multi-
component reactions ¥ solid-phase
synthesis
of novel MCRs to access polysubstituted piperidine deriva-
tives, and in particular, those possessing an a-hydroxyalkyl
side chain. Several biologically interesting alkaloids and
azasugar analogues contain a piperidine ring flanked with a
stereodefined hydroxyalkyl group at the a-position (Fig-
ure 1).[3]
Introduction
Multicomponent reactions (MCR) can be broadly defined,
regardless of their mechanistic nature, as ™one-pot∫ processes
that combine three or more substrates simultaneously.[1] The
most effective MCRs provide newproducts with optimal
change in structure and functionality from simple substrates,
and in a simple, highly atom-economical fashion. MCR
processes are particularly attractive both towards natural
product synthesis and in the more recent contexts of
combinatorial chemistry and diversity-oriented synthesis
(DOS).[2] Yet, to this day there are still only a fewversatile
MCRs displaying a wide substrate generality suitable towards
applications in DOS. We were interested in the development
HO
H
HO
CO2Me
R
N
N
N
H
H
HO
HO
HO
swainsonine
(-)-methyl palustramate
Figure 1. Selected examples of natural products containing a-hydroxyalkyl
piperidine units.
¬
[a] Prof. D. G. Hall, B. B. Toure, Dr. H. R. Hoveyda, J. Tailor,
As judged by the popularity of synthetic polysubstituted
derivatives in pharmaceutical drug development,[4] the piper-
idine subunit can be considered a privileged structure with
respect to biological properties. To the best of our knowledge,
there are very fewMCRs for the construction of piperidine
derivatives. These specific cases include the Grieco three-
component reaction[5] and a limited number of Ugi-type
condensations[6] [Eqs. (1) and (2) in Figure 2] which cannot,
however, easily accommodate the formation of an a-hydroxy-
Dr. A. Ulaczyk-Lesanko
Department of Chemistry, Gunning-Lemieux Chemistry Centre
University of Alberta, Edmonton, AB T6G 2G2 (Canada)
Fax : (‡1)780-492-8231
E-mail: dennis.hall@ualberta.ca
[b] Dr. H. R. Hoveyda
¬
Current address: Neokimia Inc.
3001 12e Avenue Nord, Fleurimont, QC J1H 5N4 (Canada)
Supporting information for this article is available on the WWW under
http://www.chemeurj.org or from the author.
466
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Chem. Eur. J. 2003, 9, No. 2

466 474
Whereas [4‡2] cycloadditions of 1-aza-1,3-butadienes[11]
and 1,3-dienylboronates[12] are known, the hybrid hetero-
dienes (e.g. 1) combining both substitution patterns are
unprecedented. The elegant work of Vaultier and others has
demonstrated the great versatility of 1,3-dienylboronates in
[4‡2] cycloadditions.[12a] From the intermediate cycloadducts,
oxidation of the boronic ester group affords secondary
alcohols, whereas allylboration of aldehydes leads to homo-
allylic alcohols in a very high diastereoselectivity. In the case
of 1-aza-4-borono-1,3-butadienes 1, we anticipated that the
tandem hetero[4‡2]/allylboration reaction planned in
Scheme 1 could be carried out as a ™one-pot∫ three-compo-
nent reaction.[13] This hypothesis was based on the premise
that the aldehyde component would not interfere with the
first stage of the tandem process, the hetero[4‡2] cyclo-
(1) Grieco three-component synthesis of piperidines[5]
O
+
PhNH2 +
Ar
H
N
Ar
H
(2) Ugi-type three-component approach to piperidines[6a,b]
COR5
R3
O
N
R3
N
R4NH
+
R4NC R5CO2H
+
R1
R2
R1
R2
(3) Petasis three-component synthesis of β-aminoalcohols[7]
R3
O
R2
R1
HO
R1
HO
+
R3B(OH)2
R2NH2
addition, for example by acting as a heterodienophile vis-a-vis
¡
+
N
H
H
heterodienes 1.
Solution-phase studies: The hydrazonodienes 1 required in
the current investigation were easily synthesized by the
condensation of aldehyde 4 with the desired hydrazines
(Scheme 2).[14] As described in our first report,[10] the common
(4) Modified Passerini MCR approach to β-aminoalcohol derivatives[8]
OCOR4
NHR3
O
R1
R1
+
R4CO2H
+
R3NC
H
PGNR2
PGNR2
O
Figure 2. Examples of multicomponent reactions.
HO
OH
O
O
B
a
b
B
alkyl side chain. Similarly, although the Petasis borono-
Mannich reaction[7] and modified Passerini condensations[8]
are powerful MCRs to access acyclic b-aminoalcohol units
[Eqs. (3) and (4)], these processes have not been applied to
the construction of a-hydroxyalkyl piperidines.[9]
EtO
OEt
CHO
CHO
2
3
4
Herein, we present a detailed study on the design and
optimization of a simple, stereoconvergent MCR strategy for
the construction of polysubstituted a-hydroxyalkyl piperi-
dines based on a tandem aza[4‡2]/allylboration reaction.[10]
O
O
B
N
c
H2N NR1R2
NR1R2
1
Scheme 2. General preparation of azadienes 1. a) i) (R)-a-pinene
(2 equiv) in THF, BH3 ¥ Me2S (1 equiv), 08C, 15 min; then RT, 2 h; add 2
(1 equiv), 08C, 1 h; then RT, 1 h; add CH3CHO (10 20 equiv), 08C; then
reflux (458C), 12 h. ii) H2O (75 equiv), 08C, 3 h (80%). b) Dry pinacol
(1 equiv), THF (100%). c) Hydrazine (1 equiv) CH2Cl2, MgSO4
(1.3 equiv), reflux, 2 h (90 95%).
Results and Discussion
Design: To access a-hydroxyalkyl piperidine derivatives in
one operation with a high degree of stereocontrol, we
envisioned a tandem reaction initiated by the hetero[4‡2]
cycloaddition of 1-aza-4-borono-1,3-butadienes (1) with ap-
propriate dienophiles that could be followed by reaction of
the allylboronate intermediates with aldehydes (Scheme 1).
precursor 4 can be made from propiolaldehyde diethyl acetal
(2) using a literature procedure involving two consecutive
distillations.[15, 16] The whole process proved rather cumber-
some and lowyielding. Since then we have improved the
synthesis of 4 by developing a simple and practical procedure
that avoids any distillation, and provides this key aldehyde 4
in high yield and purity. Hydroboration of 2 with diisopino-
campheylborane, followed by acetaldehyde promoted oxida-
tive dealkylation and hydrolysis afforded 3-boronoacrolein
(3) directly. The latter, which precipitates as a white solid
upon evaporation of the ethereal extraction layer, can be
readily separated from the residual pinene by a simple
filtration followed by washing with cold hexanes or dichloro-
methane. Formation of the corresponding ester 4 was easily
carried out by reaction with an equimolar amount of pinacol.
This key intermediate was isolated with ease in high yield, and
CO2R3
CO2R3
R4CHO
CO2R3
CO2R3
R4
HO
R4
HO
Allyl-
boration
N
N
H
NR1R2
B(OR)2
(RO)2B
N
CO2R3
CO2R3
[4+2]
CO2R3
CO2R3
+
N
NR1R2
NR1R2
1
Scheme 1. Retrosynthetic approach to substituted piperidine derivatives
using a tandem aza[4‡2]/allylboration reaction.
Chem. Eur. J. 2003, 9, No. 2
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467

D. G. Hall et al.
FULL PAPER
in essentially pure form, by evaporation of the THF solution.
Both 3 and 4 can be stored for a fewmonths at 0 8C and used
when required towards the preparation of azadienes 1. We
initially reported the preparation of these hydrazonodienes 1
by acid catalyzed condensation of aldehyde 4 with the
required hydrazines.[10] Since then, we have employed a
simpler and more efficient procedure using anhydrous
magnesium sulfate as dehydrating agent.
O
B
O
O
O
NR3
NR3
NR1R2
O
O
N
B
N
O
O
1 (Z,Z)
[4+2]
[4+2]
Fast
or
Slow
O
B
NR1R2
O
1 (E,E)
N
Maleimides were chosen as model electron-poor dieno-
philes since they are known to afford complete endo-
selectivity in their [4‡2] cycloadditions.[12a] Thus, optimization
of reaction conditions was carried out with 1-dimethylamino-
4-borono-1-azabutadiene 1a, N-phenylmaleimide, and benz-
aldehyde to give bicyclic product 5a (Table 1). By carrying out
the reaction in two distinct operations, our initial investiga-
tions indicated that the [4‡2] step proceeds rather slowly at
room temperature, and should thus be carried out at elevated
temperatures. Given that the allylboration step also occurs
above ambient temperature, we have opted for a simple one-
pot procedure[12h] in where a solution of the three reagents is
heated in toluene at 808C. It appears that the presence of the
aldehyde component does not interfere with the first,
aza[4‡2] stage of the MCR. Indeed, this one-pot procedure
provided better yields of 5a as compared to other procedures
involving the sequential addition of the dienophile followed
by the aldehyde. At the outset, we optimized the tandem
reaction using a limiting amount of the diene in order to
facilitate product purification, and also because it is the most
synthetically expensive component. The use of a 1:2:1 diene/
dienophile/aldehyde ratio and a reaction time of 72 hours
were the optimal conditions found to achieve full consump-
tion of the diene (entry 5, Table 1). Unfortunately, all our
attempts to accelerate this tandem process at lower temper-
atures through the use of Lewis acids were in vain.
NR1R2
1 (E,Z)
Scheme 3. Diene isomerization phenomena.
favoring the E,E isomer in a ratio varying between 2:1 to 5:1.
The occurrence of the minor isomer may be explained by
formation of a cyclic structure with favorable N-B coordina-
tion. At this time it is not yet possible to assess which
particular isomer between the five-membered Z,E form or the
six-membered Z,Z form is implicated. Nonetheless, the
À
presence of a C3 C4 Z isomeric form of the hydrazonodienes
was deduced from the coupling constants between all the
olefinic hydrogens. The two isomers are not isolable by
chromatography, thereby suggesting that isomerization may
be a dynamic process even at room temperature. Indeed,
recovered diene 1a from incomplete [4‡2]/allylboration
reactions carried out at 808C typically consisted of about
5:1 mixture of 3E and 3Z isomers respectively. It appears that
the 3Z isomer was not consumed in the reactions as no
cycloadducts with stereochemistry other than that expected
from the predominant E,E heterodiene were ever observed.
The lack of reactivity of the 3Z isomer could result from the
considerable steric bulk of the pinacolate ester in the endo
approach for that diene. Consequently, since the 3Z diene is
thought to interconvert readily into the reactive 3E isomer at
the reaction temperature, its presence would thus not affect
the yield of final bicyclic products 5.
Interestingly, we have noticed that some of the 4-borono-
hydrazonodienes 1 tend to undergo a thermal trans-cis
À
isomerization around the C3 C4 bond (Scheme 3). This
phenomena was particularly significant for dialkylhydrazono-
Several combinations of substrates were explored in order
to assess the generality of this tandem [4‡2]/allylboration
MCR process and its potential towards applications in
diversity-oriented synthesis (Table 2).
diene 1a, which was formed from aldehyde 4 in a mixture
The bicyclic adducts 5 were obtained following a basic
aqueous work-up required to hydrolyze the resulting pinacol
borate, and a flash-chromatographic purification. According
to 1H NMR analysis of crude reaction products, it appears that
only one stereoisomer was observed in all cases. In general,
the use of diene 1a as a limiting reagent provided modest
yields of product that were nonetheless comparable with
those reported for the reactions of 1,3-dienylboronates.[12h] On
the other hand, when excess diene 1a was used (3:1:1 diene/
dienophile/aldehyde) the yield of bicycle 5a was raised
significantly from 47 to 75% (entries 1 2, Table 2). We
suspect that heterodienes made from non-aromatic hydra-
zines (for example, 1a) are prone to thermal decomposition,
thereby causing a reduction in the yield of desired product
when they are used as limiting components. Unsurprisingly,
the maleimide substituent (R3) can be varied without affecting
product yields significantly (i.e., 5a vs 5b, entries 1 and 3). It
was found, however, that the N-aryl imide products tend to be
Table 1. Optimization of the tandem aza[4‡2]/allylboration reaction.[a]
O
O
O
B
N
O
NPh
O
+
PhCHO
NPh
O
Ph
HO
+
N
NMe2
5a
NMe2
1a
Entry
Reagent stoichiometry (equiv)
Diene 1a/N-Ph-maleimide/PhCHO
t
Yield
[%][b]
[h]
1
2
3
4
5
1:1:1
1:2:1
1:3:1
1:3:1
1:2:1
24
24
24
72
72
incompl.
incompl.
incompl.
78
80
[a] All reactions were carried out by heating a mixture of diene/dienophile/
aldehyde in anhydrous toluene [ꢀ0.2m] at 808C. [b] Crude yield of
product.
468
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Diversity-Oriented Synthesis
466 474
Table 2. Bicyclic products 5 from tandem aza[4‡2]/allylboration reactions.[a]
O
O
O
B
N
O
NR3
O
R4CHO
NR3
O
R4
HO
+
+
N
NR1R2
NR1R2
5
1
Entry
Diene
R1
Dienophile
R3
Aldehyde
R4
Ratio
Product
Yield
[%][b]
R2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
4-CF3C6H4
4-MeOC6H4
Ph
Ph
Ac
Boc
Ph
Ph
Me
Ph
Ph
Me
Ph
Me
Me
Ph
Me
Me
Ph
Ph
Ph
Ph
1:2:1
3:1:1
1:2:1
1:2:1
1:2:1
2:1:1
1:2:1
2:1:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
2:1:1
1:2:1
1:2:1
5a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o[c]
64
75
50
52
48
50
50
39
4-NO2C6H4
4-MeOC6H4
2-MeC6H4
iPrCH2
C6H11
2,4,6-Me-C6H2
Ph
Ph
76
77
55
65
68
42
61
Ph
Ph
Ph
Ph
Me
2-MeOC6H4
Ph
Ph
1g
H
[a] All reactions were carried out by heating a mixture of diene/dienophile/aldehyde in anhydrous toluene [ꢀ0.2m] at 808C for 72 h. [b] Unoptimized yields
of products isolated after flash chromatography purification. [c] This compound was characterized as its deprotected primary hydrazine derivative 6 (R2 ˆ H)
(see Scheme 4 and Experimental Section).
sensitive to hydrolysis, and must therefore be purified with
more care for characterization purposes. The isolation of
compounds 5c g (entries 4 8) shows that a wide range of
aldehydes can be employed, including aliphatic ones, as well
as both electron-rich and electron-poor benzaldehydes. Very
hindered aldehydes such as ortho-disubstituted ones (for
example, entry 9), however, failed to provide the desired
products. Although the prospect for using diverse hydrazone
substituents is irrelevant to the synthesis of free piperidines
(they are accessible through reductive cleavage of the
hydrazine), it is undoubtedly appealing towards combinato-
rial chemistry applications. Hydrazines and hydrazides are
indeed present as pharmacophores in several pharmaceuti-
cals.[17] By including both hydrazone substituents in 1 (R1, R2),
the three components in this multicomponent reaction deliver
four elements of diversity into the compact bicyclic scaffold of
anhydride, dimethyl fumarate, trans-1,2-bis(phenylsulfonyl)-
ethylene), but in all these cases the tandem reaction was either
not proceeding, or gave products that apparently decomposed
and/or gave unidentified side products at high temperatures.
Nonetheless, by offering such a wide scope of substituents for
the aldehyde and hydrazine components, this MCR offers
significant potential towards diversity-oriented syntheses of
polysubstituted piperidines derivatives. The double bond in
5b could also be selectively hydrogenated under palladium on
charcoal to provide compound 7 [Scheme 4, Eq. (2)]. X-ray
crystal structure determination[18] on the latter confirmed that
the relative stereochemistry resulting from the tandem
aza[4‡2]/allylboration reaction of dienes 1, as indicated in
Table 2, mirrors that of the carbocyclic series.[12a]
products 5. As shown with the isolation of products 5i
m
O
O
a
(entries 10 14), heterodienes 1b e made from both mono-
and disubstituted arylhydrazines are also highly effective
substrates. We observed that these heterodienes tend to show
superior thermal stability as compared to 1a and thus gave
higher yields of products in the 65 75% range even when
used as the limiting reagents. The deactivated heterodiene 1 f
made from acetylhydrazine reacted to provide product 5n
although in a modest yield (entry 15). On the other hand, a
similar diene (1g) featuring a carbamate-protected hydrazone
afforded the corresponding cycloadduct 5o in 61% yield
(entry 16). The latter was treated with trifluoroacetic acid to
provide the corresponding free primary hydrazine 6 after flash
chromatography [Scheme 4, Eq. (1)] (see also footnote [c] in
Table 2). Other dienophiles were tested (acrylates, maleic
NMe
O
NMe
O
(1)
Ph
HO
Ph
HO
N
N
NH2
HN
t-Boc
6
5o
O
O
b
NMe
O
NMe
O
(2)
Ph
Ph
N
N
N
N
HO
Me
HO
Me
Me
Me
5b
7
Scheme 4. Transformations of tandem aza[4‡2]/allylboration products.
a) CF3CO2H/H2O 95:5, RT, 2 h (50%). b) H2 (1 atm), 10% Pd(C), EtOH,
RT, 18 h (72%).
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D. G. Hall et al.
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Mechanistically, the [4‡2] cycloaddition of heterodienes 1
with maleimides is expected to proceed with complete endo-
selectivity to give the allylboronate intermediate shown in
Figure 3. From the latter, the stereochemical outcome of the
of the three components must be tethered to the solid support.
The substrate to be conjugated to the support must be
bifunctional, and since its immobilization usually impedes its
use as a diversifiable element, it is most advantageous to avoid
sacrificing those components that are the most easily acces-
sible as cheap, commercial building blocks. Considering that
there are far more commercial aldehyde and hydrazine
building blocks as compared to N-substituted maleimides,
we chose to tether the latter to the support. To this end, we
made use of our recently published methodology for mal-
eidobenzoic acid (MBA) resins.[23] Thus, optimization of the
solid-supported aza[4‡2]/allylboration MCR was carried out
using SASRIN-p-MBA resin 12, diene 1a, and benzaldehyde
(Scheme 6).
(RO)2B
O
O
O
(RO)2B
H
NR3
R4
N
R4CHO
NR3
H
H
O
N
NR1R2
H
O
NR1R2
H
H
O
O
O
(RO)2B
NR3
NR3
H
H
R4
R4
N
NR1R2
N
O
O
O
H
NR1R2
H
H
(RO)2B
H
O
N
O
O
N
O
Figure 3. Proposed transition state to rationalize the stereochemistry
resulting from the allylboration step.
1a, PhCHO
O2C
O2C
Ph
OH
N
Me2N
12
allylation step can be explained via the usual cyclic chair-like
allylboration transition state involving anti coordination of
the aldehyde to the boronyl group oriented axially on the
endo face of the piperidine ring. It is noteworthy that this
system constitutes a rare example of allylboration reaction
involving g-amino-substituted allylboryl substrates.[19, 20]
Moreover, the stereochemistry of the resulting 1,2-amino-
alcohol unit is the same as that of several alkaloids including
swainsonine and methyl palustramate (Figure 1), thus con-
firming the potential of this strategy in natural product
synthesis.
In addition to the high level of diastereoselectivity observed
in this tandem hetero[4‡2]/allylboration process, it was also
possible to control the absolute stereochemistry of the bicyclic
structure using a chiral auxiliary approach. While l-proline
derived diene 8 failed to give 9 in high de, the dimethyl
analogue 10 was reacted with N-phenylmaleimide, and
benzaldehyde to provide bicycle 11 in a remarkable >95%
de (Scheme 5).[21, 22]
13
O
N
O
O
N
O
0.5% TFA/CH2Cl2
HO2C
+
HO2C
Ph
OH
N
Me2N
15
14a
Scheme 6. Optimization of the solid-phase reaction.
Several experiments were performed whereby the relative
stoichiometry of the three components, temperature, and time
were varied with the goal of identifying the mildest, most
economical reaction conditions that would provide full
conversion of the resin bound maleimide (Table 3). Following
the usual resin rinses, cleavage of supported material 13 to
give 14a was effected with 0.5% trifluoroacetic acid in
dichloromethane followed by HPLC analysis (both UV and
ES-MS). Inasmuch as absence of cleaved maleimide 15 from
the crude product represents a complete reaction, these assays
confirmed that the solid-phase tandem reaction was indeed
faster than its solution-phase counterpart. This effect is likely
due to the use of excess reagents and also to the use of a more
electron-poor N-(p-carboxyphenyl)imide dienophile. While the
conditions of entry 1 (72 hours at 808C) were a prerequisite to
ensure reaction completion in the solution-phase variant, we
were able to significantly reduce the reaction time to 14 h and
O
O
O
B
O
NPh
a
Ph
HO
N
N
+
NPh
O
+
PhCHO
O
N
N
C(R)2OMe
R
R
OMe
8: (R = H)
10: (R = Me)
9: (80% de)
11: (> 95% de)
Table 3. Optimization of the tandem aza[4‡2]/allylboration reaction on
solid-phase.[a]
Scheme 5. Tandem aza[4‡2]/allylboration reaction of chiral dienes 8 and
10. a) Conditions of Table 1; (55% for 11).
Entry
Reagent stoichiometry (equiv)
T
t
Outcome[b]
MBA resin 12/diene 1a/PhCHO
[8C]
[h]
1
2
3
4
5
6
1:20:20
1:20:20
1:20:20
1:20:20
1:10:10
1:5:10
80
80
80
40
80
80
72
24
14
14
14
14
full conversion
full conversion
full conversion
incomplete
full conversion
full conversion
Solid-phase studies: The possibility of carrying out this
aza[4‡2]/allylboration MCR on solid support could signifi-
cantly simplify its application to the generation of parallel
libraries of polysubstituted piperidine derivatives. In partic-
ular, the use of excess reagents, which can be easily eliminated
through simple resin washes, could help drive forward the
tandem process and shorten the long reaction times required
for the solution phase reaction. From a design standpoint, one
[a] All reactions were carried out by heating a mixture of SASRIN MBA
resin 12:diene 1a:benzaldehyde in anhydrous toluene [ꢀ0.2m] at 808C.
[b] The extent of conversion was determined by HPLC (UV and ES-MS).
470
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Chem. Eur. J. 2003, 9, No. 2

Diversity-Oriented Synthesis
466 474
phase reactions were carried out in silanized glass vessels or in small
polypropylene (PP) filter vessels (Bio-Rad). In the latter case, agitation of
the vessels was provided by an orbital shaker. The workups of solid-
supported reactions were carried out by rinsing the resin several times with
different solvents (usually toluene, methanol, and methylene chloride).
Acetone, CH2Cl2, and toluene were freshly distilled from calcium hydride
prior to use. Anhydrous THF was distilled from sodium/benzophenone in a
recycling still. Reagents and starting materials were obtained from
commercial suppliers and used without further purification unless other-
wise noted. Pinacol was recrystallized from dichloromethane and dried
under vacuum. All organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated with a rotary evaporator under reduced pressure.
Chromatography refers to flash chromatography on silica gel (230
400 mesh). Thin-layer chromatography (TLC) was performed on 0.25 mm
Merck precoated silica-coated plates (60F-254). Visualization was obtained
by exposure to 5% phosphomolybdic acid in ethanol or aqueous KMnO4
solution. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded at 300, 400, or 500 MHz in CDCl3 as solvent unless otherwise
mentioned. Protons chemical shifts are expressed in parts per million
(ppm) and recorded relative to tetramethylsilane as an internal standard.
Coupling constants are expressed as J values in hertz units (Hz) and are
accurate to Æ0.4 0.6 Hz. The following abbreviation are used: s ˆ singlet,
d ˆ doublet, dd ˆ doublet of doublet, ddd ˆ doublet of doublet of doublet,
t ˆ triplet, m ˆ multiplet and br ˆ broad. For broad singlets and sym-
metrical multiplets, only the central shift value may be provided, while a
shift range was provided for borader unsymmetrical signals. 13C NMR
spectra were recorded on a Bruker WH-300 (75 MHz) NMR spectrometer
in CDCl3 as solvent, and chemical shifts are expressed in ppm. Infrared
spectra were obtained on a Nicolet Magna-IR 750. Frequencies are
expressed in cmÀ1. Melting points were determined in a capillary tube on a
Gallenkamp melting point apparatus and are uncorrected. Elemental
analyses (C, H, N) were performed by the microanalytical laboratory of our
department. High resolution electrospray mass spectra (HRMS) were
obtain cleaner product by using a 20-fold excess of reagents.
Furthermore, as shown with entry 6 (Table 3), full conversion
was maintained by using a smaller amount of the diene
(5 equiv). In the end, the parameters of entry 6 were selected
as the optimal reaction conditions for this solid-phase MCR
process. In addition, we found much to our surprise that the
basic treatment required to hydrolyze the final borate
intermediate in solution phase was not necessary in the
solid-phase variant. This could be explained by the use of
excess methanol during the resin rinsing operations, which
may cause transesterification of the borate ester.
We have examined substrate generality in the solid-phase
MCR, although in less detail since this issue was thoroughly
studied in the solution phase. All three piperidine derivatives
14a 14c were obtained in moderate crude yields following
cleavage from the solid support (Figure 4). Furthermore,
according to HPLC-MS analysis, the compounds were iso-
lated with a reasonable level of purity (80 90%) typically
suitable towards HTS of combinatorial libraries. In the design
of such libraries, however, it may be advisable to consider the
synthesis of more hydrolytically stable N-alkyl imide products
(see above) from supported N-alkylmaleimide dienophiles.
O
N
O
O
N
O
HO2C
HO2C
Ar
OH
Ph
OH
N
N
N
Me2N
Ph
H
obtained on
a
Micromass ZabSpec oa TOF instrument. Significant
14a: Ar = C6H5 (62%)
14b: Ar = 4-Br-C6H4 (54%)
‡
14c (60%)
protonated molecular ions [M‡H] as well as peaks corresponding to
‡
sodiated molecular ions [M‡Na] were present in most of the spectra
Figure 4. Polysubstituted piperidines synthesized on solid-support.
because of trace amounts of sodium salts in the samples. X-ray analysis was
performed on a Bruker SMART 1000/P4/RA diffractometer by Dr. R.
MacDonald at the University of Alberta.
3-Borono-acrolein (3): A 100 mL round bottom flask equipped with a
septum inlet was charged with borane/dimethylsulfide complex (10m stock
solution, 3.3 mL, 33 mmol) and tetrahydrofuran (THF) (10 mL) under
nitrogen. (R)-(‡)-a-pinene (91% ee) (10.8 mL, 66.7 mmol) was then added
dropwise at 08C. The mixture was stirred for 10 min followed by 2 h at
room temperature. The resulting white diisopinocampheylborane suspen-
sion was cooled to 08C and propiolaldehyde diethyl acetal (4.5 mL,
31 mmol) was added slowly. The resulting mixture was stirred at 08C for 1 h
and further stirred at room temperature for an additional 1 h, and cooled
back to 08C again prior to the quick addition of freshly distilled
acetaldehyde (20 mL). The solution was stirred for 30 minutes, warmed
up, then the flask was fitted with a condenser and heated to 458C overnight.
The solution obtained was cooled to 08C, and water (12 mL) was added.
After 3 h, the solution was transferred to a separatory funnel. The aqueous
phase was extracted two times with Et2O (50 mL) and ethyl acetate
(50 mL). The combined organic layers were concentrated under reduced
pressure. Under these conditions, the boronic acid precipitates as a white
solid. It was then separated from pinene by addition of either cold hexane
or cold dichloromethane and filtration (2.5 g, 76%).
Conclusion
In summary, we have described the first three-component
aza[4‡2]/allylboration reaction to access polysubstituted a-
hydroxyalkyl piperidines in a highly diastereocontrolled
fashion from maleimides, 4-boronohydrazonodienes, and
aldehydes. The required 4-borono-hydrazonodienes are syn-
thesized efficiently from the condensation of 3-boronoacro-
lein pinacol ester (4) with hydrazines. Overall the tandem
aza[4‡2]/allylboration process is quite general. It tolerates
the use of a wide variety of aldehydes and hydrazine
precursors with different electronic and steric characteristics.
By allowing a wide substrate scope and up to four elements of
diversity, this MCR is particularly well adapted towards
applications in diversity-oriented synthesis of polysubstituted
piperidine derivatives. The suitability of this MCR for use in
solid-phase chemistry was also demonstrated using an N-ar-
ylmaleidobenzoic acid functionalized resin. Fewmulticompo-
nent reactions offer such a high level of stereocontrol and
versatility in the preparation of densely functionalized nitro-
gen heterocycles.
Pinacol ester 4: The 3-boronoacrolein (3) (1.00 g, 10.0 mmol) was dissolved
in THF (25 mL) at room temperature, and dry pinacol (recrystallized from
dichloromethane) (1.12 g, 10.0 mmol) was added. The solution was stirred
for 30 minutes then the solvent was evaporated under reduced pressure at
458C to afford a colourless oil in quantitative yield. Addition of THF
followed by concentration may be necessary to complete the condensation
by azeotropic removal of the water.
Typical procedure for the preparation of 4-borono heterodienes 1a e:
Preparation of N,N-dimethylhydrazonodiene 1a: N,N-dimethylhydrazine
(0.42 mL, 5.5 mmol) and magnesium sulfate (0.86 g, 7.2 mmol) were added
to a solution of aldehyde 4 (1.0 g, 5.5 mmol) in freshly distilled dichloro-
methane. The resulting mixture was then heated under reflux for 2 h.
Magnesium sulfate was removed by filtration through a predried fritted
Experimental Section
General: Unless otherwise noted, all operations were carried out in oven or
flame-dried glassware under a dry, oxygen-free nitrogen atmosphere. Solid-
Chem. Eur. J. 2003, 9, No. 2
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0902-0471 $ 20.00+.50/0
471

D. G. Hall et al.
FULL PAPER
funnel. Solvent was evaporated under reduced pressure to afford a
yellowish oil as the product (1.2 g, 90%).
of sodium hydrogen carbonate. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (3 Â 15 mL each). The combined
organic layers were dried over anhydrous magnesium sulfate, filtered, and
concentrated to afford 5 as a crude product. Purification by flash column
chromatography using 1% MeOH in dichloromethane (or EtOAc/hexanes
system) led to the isolation of the pure product 5 as pale yellowsolid in 42
77% yield (see Table 2).
All dienes 1a e were isolated as a mixture of two inseparable 3E and 3Z
isomers (see text). NMR assignments are provided only for the major (E,E)
isomers. These dienes were generally employed immediately in the tandem
reactions.
Spectroscopic data for 1a (90% yield): IR (CHCl3 cast): nÄ ˆ 2977, 2931,
2865, 1548, 1412, 1213, 998, 882, 779 cmÀ1 1H NMR (300 MHz, CDCl3):
;
Spectroscopic data for 5a: m.p. 80 828C; IR (CHCl3 cast): nÄ ˆ 3475, 2944,
1
1783, 1597, 1454, 1199, 1059, 864, 667, 646, 621 cmÀ1; H NMR (300 MHz,
d ˆ 7.15 (dd, J ˆ 8.9, 17.9 Hz, 1H), 6.93 (d, J ˆ 8.9 Hz, 1H), 5.53 (d, J ˆ
17.9 Hz, 1H), 2.95 (s, 6H), 1.22 (s, 12H); 13C (75 MHz, CDCl3, APT): d ˆ
148.2 (CH), 135.6 (CH), 134.5 (CH), 83.0 (C), 42.4, 24.9; MS (ES): m/z: 225
CDCl3): d ˆ 7.25 7.55 (m, 10H), 6.01 (ddd, J ˆ 1.5, 3.7, 10.5 Hz, 1H), 5.75
(ddd, J ˆ 1.5, 4.3, 10.6 Hz, 1H), 4.62 (d, J ˆ 8.4 Hz, 1H), 4.24 (brs, 1H,
OH), 3.89 (d, J ˆ 9.5 Hz, 1H), 3.62 3.58 (m, 1H), 3.54 3.48 (m, 1H), 2.50
(s, 6H); 13C (75 MHz, CDCl3, APT): d ˆ 176.1, 174.0(CO), 140.1, 131.6 (C),
130.6, 129.2, 128.7, 128.5, 128.2, 127.2, 126.3, 121.1, 76.6, 61.4, 57.2, 43.7 (N-
‡
[M‡H] ; HRMS (ES): m/z: calcd for C11H22BN2O2: 225.1774; found:
‡
225.1778 [M‡H] .
Spectroscopic data for 1b (86% yield): IR (CHCl3 cast): nÄ ˆ 3285, 2977,
‡
‡
CH3), 38.9 (CH); MS (ES): m/z: 400 [M‡Na] , 378 [M‡H] , 360[M À
2924, 1560, 1446, 1286, 1214, 1070, 899, 648 cmÀ1 1H NMR (300 MHz,
;
‡
H2O] ; HRMS (ES): m/z: calcd for C22H23N3O3Na: 400.1637; found:
CDCl3): d ˆ 7.34 7.21 (m, 5H), 6.99 (d, J ˆ 9.0 Hz, 1H), 6.87 (dd, J ˆ 9.0,
18.0 Hz, 1H), 5.68 (d, J ˆ 18.0 Hz, 1H), 1.25 (s, 12H); 13C (75 MHz, CDCl3,
APT): d ˆ 146.4 (CH), 143.9 (C), 139.9 (CH), 129.2 (CH), 120.6 (CH), 120.4
‡
400.1639 [M‡Na] .
Spectroscopic data for 5b: m.p. 110 1128C; IR (CHCl3 cast): nÄ ˆ 3463,
‡
(CH), 112.1 (CH), 82.7 (C), 24.7; MS (ES): m/z: 305 [M‡Na] , 273
2945, 1779, 1704, 1454, 1434, 1279, 1199, 1124, 990, 809, 775, 703 cmÀ1
;
‡
[M‡H] ; HRMS (ES): m/z: calcd for C15H22BN2O2: 273.1774; found:
1H NMR (300 MHz, CDCl3): d ˆ 7.35 7.25 (m, 5H), 5.91 (dd, J ˆ 2.2,
10.4 Hz, 1H), 5.63 (ddd, J ˆ 2.2, 4.5, 11.6 Hz, 1H), 4.42 (d, J ˆ 9.1 Hz, 1H),
4.26 (brs, 1H, OH), 3.73 (d, J ˆ 9.6 Hz, 1H), 3.46 3.40 (m, 2H), 3.05 (s,
3H) 2.46 (s, 6H); 13C (75 MHz, CDCl3, APT): d ˆ 177.0, 175.1 (CO), 140.2
(C), 130.2, 128.4, 128.1, 127.1, 121.2, 75.6, 61.2, 57.3, 38.7 (CH), 43.7 [N-
‡
273.1769 [M‡H] .
Spectroscopic data for 1c (83% yield): 1H NMR (400 MHz, CDCl3): d ˆ
7.80 (s, 1H), 7.48 (d, J ˆ 6.8 Hz, 2H), 7.42 (d, J ˆ 7.5 Hz, 2H), 7.20 (dd, J ˆ
7.2, 14.6 Hz, 1H), 7.04 (d, J ˆ 6.8, 1H), 5.75 (d, J ˆ 14.5 Hz, 1H), 1.23 (s,
12H); 13C (75 MHz, CDCl3): d ˆ 147.0, 146.6, 141.7, 126.5, 122.7 (q), 112.6,
111.2, 83.6, 25.1; HRMS (EI): m/z: calcd for C16H20BF3N2O2: 340.1570;
‡
‡
N(CH3)2], 25.3 (N-CH3); MS (ES): m/z: 338 [M‡Na] , 316 [M‡H] ;
HRMS (ES): m/z: calcd for C17H21N3O3Na: 338.1481; found: 338.1481
[M‡Na] ; elemental analysis calcd (%) for C17H21N3O3 (315.16): C 64.8, H
‡
‡
found: 340.1572 [M] .
6.7, N, 13.3; found: C 64.1, H 6.6, N 12.6.
Spectroscopic data for 1d (88% yield): 1H NMR (300 MHz, CDCl3): d ˆ
7.60 7.46 (brs, 1H), 7.36 (d, J ˆ 9.0 Hz, 1H), 7.19 (dd, J ˆ 9.2, 18.3 Hz, 1H),
6.94 (d, J ˆ 9.0 Hz, 2H), 6.80 (d, J ˆ 9.0 Hz, 2H), 5.63 (d, J ˆ 17.7 Hz, 1H),
3.68 (s, 3H), 1.25 (s, 12H); 13C (75 MHz, CDCl3, APT): d ˆ 154.2 (C), 146.5
(CH), 139.3 (CH), 138.0 (C), 114.8 (CH), 114.6 (CH), 114.1 (CH), 83.4 (C),
55.6 (CH3), 24.7 (CH3); HRMS (ES): m/z: calcd for C16H23BN2O3:
Spectroscopic data for 5c: m.p. 90 928C; IR (CHCl3 cast): nÄ ˆ 3439, 2922,
2852, 1778, 1597, 1499, 1376, 1197, 1108, 1072, 752, 691 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d ˆ 8.40 (d, J ˆ 7.2 Hz, 2H), 7.55 7.38 (m, 5H), 7.29 (d,
J ˆ 6.8 Hz, 2H), 6.08 (dd, J ˆ 3.7, 10.6 Hz, 1H), 5.75 (ddd, J ˆ 1.5, 3.9,
9.8 Hz, 1H), 4.60 (d, J ˆ 8.4 Hz, 1H), 4.14 4.04 (m, 1H), 4.02 (d, J ˆ
9.3 Hz, 1H), 3.66 3.56 (m, 1H), 3.52 3.43 (m, 1H), 2.47 (s, 6H); 13C
(75 MHz, CDCl3): d ˆ 176.1, 173.6, 155.8, 147.8, 131.5 (2), 130.5, 129.7, 129.3,
129.1, 127.8, 126.5, 126.1, 123.7, 75.5, 60.4, 56.3, 43.6 [N-N(CH3)2], 39.1; MS
‡
302.1800; found: 302.1799 [M] .
Spectroscopic data for 1e (81% yield): IR (CHCl3 cast): nÄ ˆ 2977, 2926,
1651, 1611, 1552, 1457, 1215, 1030, 897, 668, 648 cmÀ1; 1H NMR (300 MHz,
CDCl3): d ˆ 7.25 (m, 5H), 6.98 6.89 (m, 2H), 5.70 (d, J ˆ 15.3 Hz, 1H),
3.34 (s, 3H), 1.26 (s, 12H); 13C (75 MHz, CDCl3, APT): d ˆ 152.6 (C), 148.4
(CH), 135.7 (CH), 128.8 (CH), 118.4 (CH), 115.6 (CH), 114.8 (CH), 83.1
‡
‡
(ES): m/z: 445 [M‡Na] , 423 [M‡H] ; HRMS (ES): m/z: calcd for
‡
C22H22N4O5Na: 445.1488; found: 445.1482 [M‡Na] .
Spectroscopic data for 5d: m.p. 107 1108C; IR (CHCl3 cast): nÄ ˆ 3476,
‡
1
(C), 44.3, 24.7; MS (ES): m/z: 287 [M‡H] ; HRMS (ES): m/z: calcd for
2919, 2850, 1651, 1597, 1513, 1302, 1137, 832, 806, 692, 405 cmÀ1; H NMR
‡
C16H24BN2O2: 287.1931; found: 287.1938 [M‡H] .
(300 MHz, CDCl3): d ˆ 7.50 7.35 (m, 5H), 7.30 7.20 (m, 4H), 6.75 (d, J ˆ
6.0 Hz, 2H), 5.98 (ddd, J ˆ 1.1, 3.6, 10.6 Hz, 1H), 5.71 (ddd, J ˆ 2.3, 4.6,
10.5 Hz, 1H), 4.60 (d, J ˆ 8.5 Hz, 1H), 3.88 (s, 1H), 3.82 (d, J ˆ 9.1 Hz, 1H),
3.77 (s, 3H), 3.53 3.51 (m, 1H), 3.51 3.44 (m, 1H), 2.50 (s, 6H); 13C
(75 MHz, CDCl3, APT): d ˆ 176.0, 174.0 (CO), 159.6, 132.1, 131.6 (C),
130.7, 129.3, 128.9, 128.3, 126.2, 121.1, 113.9, 75.6, 61.5, 57.2, 55.3 (CH), 43.7
Spectroscopic data for 1g (93% yield): IR (CH2Cl2 cast): nÄ ˆ 3231, 2933,
1619, 1480, 1457, 1215, 1048, 1020, 900, 866, 764, 588, 457 cmÀ1 1H NMR
;
(500 MHz, CDCl3): d ˆ 7.87 (s, 1H), 7.43 (d, J ˆ 7.5 Hz, 1H), 7.08 (dd, J ˆ
9.5, 17.9 Hz, 1H), 5.76 (d, J ˆ 18.0 Hz, 1H), 1.44 (s, 9H), 1.20 (s, 12H); 13
C
(125 MHz, CDCl3, APT): d ˆ 154.2 (C), 146.1 (CH), 145.5 (CH), 145.4
‡
‡
[N-N(CH3)2], 38.8 (OCH3); MS (ES): m/z: 430 [M‡Na] , 408 [M‡H] , 390
(CH), 83.7 (C), 81.7 (C), 28.3 (CH3), 24.8 (CH3); HRMS (ES): m/z: calcd
‡
‡
[M À H2O] ; HRMS (ES): m/z: calcd for C23H25N3O4Na: 430.1743; found:
for C14H25BN2O4Na: 319.1799; found: 319.1802 [M‡Na] ; elemental
‡
430.1742 [M‡Na] .
analysis calcd (%) for C14H25BN2O4 (296.17): C 56.72, H 8.51, N 9.49;
found: C 56.06, H 8.51, N 9.28.
Spectroscopic data for 5e: FTIR (CHCl3 cast): nÄ ˆ 3471, 2946, 2817, 2776,
1780, 1705, 1434, 1374, 1279 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 7.50
Procedure for the preparation of diene 1 f: Acetic hydrazide (0.41 g,
5.55 mmol) was added to a solution of aldehyde 4 (1.01 g, 5.55 mmol) in
anhydrous EtOH (20 mL). The mixture was stirred vigorously for 1 h under
refluxing conditions (858C), after which time it was allowed to cool down to
RT. The solution was then evaporated and dried over vacuum to give crude
product 1 f as a pale yellowsolid. The crude product was subjected to flash
chromatography on silica gel, eluting with 10% MeOH in dichloro-
methane, giving pure heterodiene 1 f in 62% yield. IR (CHCl3 cast): nÄ ˆ
(dd, J ˆ 1.2, 8.7 Hz, 1H), 7.20 (dd, J ˆ 1.2, 6.8 Hz, 1H), 7.13 (dt, J ˆ 1.5,
7.5 Hz, 1H), 7.04 (d, J ˆ 7.2 Hz, 1H), 5.85 (ddd, J ˆ 1.5, 3.9, 10.5 Hz, 1H), 5.6
(ddd, J ˆ 2.1, 4.7 and 10.5 Hz, 1H), 4.50 (d, J ˆ 8.4 Hz), 4.1 (d, J ˆ 9.9 Hz,
1H), 3.55 3.50 (m, 1H), 3.47 3.39 (m, 1H), 3.05 (s, 3H), 2.50 (s, 6H), 2.10
(s, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 177.1, 175.0, 138.3, 135.3, 130.4,
130.2, 127.7, 126.6, 126.5, 70.4, 61.4, 57.2, 43.8, 38.7, 25.2, 19.4; HRMS (EI):
‡
m/z: calcd for C18H23N3O3: 329.1740; found: 329.1741 [M] ; elemental
3205, 2978, 1958, 1618, 1560, 1270, 1214, 898, 667, 649 cmÀ1 1H NMR
;
analysis calcd (%) for C18H23N3O3 (329.17): C 65.65, H 6.99, N 12.76; found:
C 65.52, H 6.92, N 12.62.
(300 MHz, CDCl3): d ˆ 7.42 (d, J ˆ 9.1 Hz, 1H), 7.06 (dd, J ˆ 8.8, 18.0 Hz,
1H), 5.92 (d, J ˆ 18.0 Hz, 1H), 3.47 (s, 3H), 1.23 (s, 12H); 13C (75 MHz,
CDCl3, APT): d ˆ 174.3 (CO), 146.5 (CH), 146.2 (CH), 145.0 (CH), 83.7
Spectroscopic data for 5 f: m.p. 75 788C; IR (CHCl3 cast): nÄ ˆ 2953, 1777,
1713, 1597, 1499, 1455, 1383, 1180, 751, 691 cmÀ1 1H NMR (300 MHz,
;
‡
‡
(C), 24.8, 20.2; MS (ES): m/z: 261 [M‡Na] , 239 [M‡H] ; HRMS (ES):
CDCl3): d ˆ 7.58 7.25 (m, 5H), 6.17 (dddd, J ˆ 0.9, 2.2, 4.6, 8.4 Hz, 1H),
6.04 (ddd, J ˆ 2.1, 4.0, 10.5 Hz, 1H), 4.52 (d, J ˆ 8.6 Hz, 1H), 3.54 (m, 1H),
3.24 (m, 2H), 2.52 2.49 (m, 1H), 2.51 (s, 6H), 1.91 (m, 1H), 1.22 (m, 2H),
0.92 (s, 6H); 13C (75 MHz, CDCl3, APT): d ˆ 176.4, 174.1 (CO), 131.6 9 (C),
130.9, 129.2, 129.1, 126.2, 121.2, 70.7, 60.0, 57.3, 56.3, 43.7 (CH), 42.4 (CH2),
‡
m/z: calcd for C11H20BN2O3: 239.1567; found: 239.1564 [M‡H] .
General solution-phase procedure for the preparation of bicyclic piperidine
products 5a o, 9, 11: The aldehyde (1 equiv) was added under a nitrogen
atmosphere at room temperature to a solution of diene 1 (1 or 2 equiv) in
toluene (5 mL). The dienophile (1 or 2 equiv) was added to the above
mixture which was then heated at 808C for 3 d, then allowed to cool down
to RT diluted with EtOAc, and stirred for 30 min with a saturated solution
‡
38.6 [N-N(CH3)2], 24.6, 23.9 (CH3); MS (ES): m/z: 380 [M‡Na] , 358
‡
[M‡H] ; HRMS (ES): m/z: calcd for C20H28N3O3: 358.2131; found:
‡
358.2136 [M‡H] .
472
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0902-0472 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 2

Diversity-Oriented Synthesis
466 474
Spectroscopic data for 5g: IR (CHCl3 cast): nÄ ˆ 3495, 2927, 2851, 2772, 1781,
174.0, 173.4, 169.6 (CO), 136.9, 136.0 (C), 131.4, 129.1, 128.7, 128.5, 128.4,
1705, 1434, 1376, 1278 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 6.05 (ddd,
127.6, 127.4, 121.0, 77.5, 61.8, 58.7, 39.8 (CH), 21.1 (COCH3); MS (ES): m/z:
J ˆ 2.1, 4.8, 10.5 Hz, 1H), 5.94 (ddd, J ˆ 1.2, 3.9, 10.5 Hz, 1H), 4.38 (d, J ˆ
8.7 Hz, 1H), 3.48 3.42 (m, 2H), 3.40 3.36 (m, 1H), 2.95 (s, 3H), 2.60 (d,
J ˆ 9 Hz, 1H), 2.48 (s, 6H), 1.78 1.09 (five m×s, 11H); 13C NMR (75 MHz,
CDCl3): d ˆ 177.2, 175.1, 130.7, 121.1, 76.1, 56.7, 43.6, 39.1, 38.6, 31.2, 26.8,
26.4, 25.3, 25.2; HRMS (EI): m/z: calcd for C17H27N3O3: 321.2052; found:
321.2058; elemental analysis calcd (%) for C17H27N3O3 (321.20): C 63.55, H
8.41, N 13.03; found: C 63.57, H 8.49, N 13.07.
‡
414 [M‡Na] ; HRMS (ES): m/z: calcd for C22H21N3O4Na: 414.1430;
‡
found: 414.1430 [M‡Na] .
Spectroscopic data for 5o (6): Although compound 5o shows correct MS
data (see HPLC-ESMS chromatogram in Supporting Information), it exists
as a mixture of rotamers that complicate NMR spectra. Therefore it was
rather characterized as a free hydrazine derivative (6) following cleavage of
the Boc group: A mixture of trifluoroacetic acid and water (95:5, 10 mL)
was added to 5o (0.327 g, 0.85 mmol) at 08C under N2. The reaction
mixture was warmed up to RT and stirred for 2 h. After completion, the
reaction mixture was dried with MgSO4, filtered, and benzene (50 mL) was
added to the filtrate. The solvents were removed in vacuo (this was
repeated twice) to give a brown solid as the crude product (0.300 g). The
crude product was purified by flash chromatography with 5% MeOH in
CH2Cl2 as solvents system, and pure free primary hydrazine compound 6
was obtained (0.126 g, 50%). Spectroscopic data for 6: m.p. 178 1818C; IR
(CH2Cl2 cast): nÄ ˆ 3348, 3059, 2879, 1778, 1602, 1494, 1225, 1198, 1055, 985,
910, 817, 799, 764, 734, 669, 619, 552 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ
7.45 7.20 (m, 5H), 5.92 (ddd, J ˆ 2.4, 2.6, 10.2 Hz, 1H), 5.32 5.23 (m, 1H),
4.48 (d, J ˆ 8.7, 1H), 3.59 (d, J ˆ 7.5 Hz, 1H), 3.39 3.25 (m, 2H), 3.00 (s,
3H); 13C (100 MHz, CDCl3, APT): d ˆ 174.9 (C), 140.6 (C), 128.5 (CH),
128.2 (CH), 127.6 (CH), 119.0 (C), 78.7 (CH), 66.7 (CH), 65.1 (CH), 41.3
Spectroscopic data for 5i: m.p. 180 1828C; IR (CHCl3 cast): nÄ ˆ 3515,
3028, 2920, 1715, 1600, 1495, 1454, 1384, 1371, 1247, 1195, 1058, 971, 828,
751, 699 cmÀ1; 1H NMR (300 MHz, CDCl3 ‡ D2O): d ˆ 7.49 6.92 (m, 15H),
6.23 6.17 (m, 1H), 5.59 (ddd, J ˆ 2.2, 4.4, 10.4 Hz, 1H), 4.61 (d, J ˆ 9.2 Hz,
1H), 4.22 (d, J ˆ 9.6 Hz, 1H,), 3.91 (brs, 1H, OH), 3.85 3.71 (m, 2H); 13
C
(75 MHz, CD2Cl2): d ˆ 173.6, 173.5 (CO), 147.1 139.4, 131.3 (C), 129.6,
129.4, 129.3, 129.1, 128.6, 128.4, 127.1, 126.2, 126.1, 121.1, 114.13, 76.3, 68.1,
‡
68.0, 38.3 (CH); MS (ES): m/z: 448 [M‡Na] ; HRMS (ES): m/z: calcd for
‡
C26H23N3O3Na: 448.1637; found: 448.1636 [M‡Na] ; elemental analysis
calcd (%) for C26H23N3O3 (425.17): C 73.5, H 5.4, N 9.9; found: C 73.2, H
5.2, N 9.6.
Spectroscopic data for 5j: FTIR (CHCl3 cast): nÄ ˆ 3464, 3246, 2920, 1958,
1784, 1705, 1617, 1527, 1495, 1431, 1413, 1385, 1275 cmÀ1 1H NMR
;
(300 MHz, CD3COCD3): d ˆ 7.48 (d, J ˆ 8.6, 2H), 7.45 7.21 (m, 5H), 7.16
(d, J ˆ 8.3 Hz, 2H), 6.03 (ddd, J ˆ 1.3, 4.4, 10.4 Hz, 1H), 5.58 (ddd, J ˆ 2.2,
4.4, 10.5 Hz, 1H), 4.50 (d, J ˆ 8.2 Hz, 1H), 4.26 (s, 1H), 4.21 (brs, 1H),
3.75 3.58 (m, 2H), 2.97 (s, 3H); 13C NMR (75 MHz, CD3COCD3): d ˆ
176.6, 175.3, 151.6, 141.6, 128.8, 128.4, 127.9, 126.9, 123.0, 120.4 (q), 113.3,
113.2, 76.2, 76.1, 62.3, 38.0, 25.1; HRMS (EI): m/z: calcd for C22H20F3N3O3:
‡
(CH), 25.1 (CH3); MS (ES): m/z: 288 [M‡H] ; HRMS (ES):: m/z: calcd for
‡
C15H17N3O3Na: 310.1167; found: 310.1660 [M‡Na] .
Preparation of 7: Compound 5b (0.16 g, 0.51 mmol) dissolved in EtOH
(2 mL) was added under an H2 atmosphere to a suspension of 10% Pd on
carbon (0.16 g) in EtOH (3 mL). After 18 h of stirring at RT, the catalyst
was filtered out. The solution was concentrated and purified by chroma-
tography on silica gel (5% MeOH in dichloromethane) affording 7 as pale
yellow solid (0.12 g, 75%), which was crystallized from dichloromethane
(RT).
‡
431.1457; found: 431.1471 [M] ; elemental analysis calcd (%) for
C22H20F3N3O3 (431.15): C 61.25, H 4.64, N 9.74; found: C 61.1, H 4.51, N
9.64.
Spectroscopic data for 5k: m.p. 2108C (decomp.); IR (CH2Cl2 cast): nÄ ˆ
2827, 1771, 1604, 1299, 1205, 1167, 995, 918, 902, 878, 677, 619, 599, 561 cmÀ1
;
Spectroscopic data for 7: m.p. 138 1408C; IR (CHCl3 cast): nÄ ˆ 3018, 2916,
1H NMR (400 MHz, CDCl3): d ˆ 7.25 7.12 (m, 5H), 6.97 6.92 (m, 2H),
6.82 6.76 (m, 2H), 6.15 6.05 (m, 1H), 5.45 (ddd, J ˆ 2.2, 4.7, 10.4 Hz, 1H),
4.39 (d, J ˆ 8.3 Hz, 1H), 4.09 3.95 (m, 1H), 3.71 (s, 3H), 3.58 (m, 1H),
3.54 3.44 (brs, 1H), 3.00 (s, 3H); 13C (75 MHz, CDCl3): d ˆ 174.7 (CO),
154.7 (C), 139.5 (C), 128.5 (CH), 128.3 (CH), 127.1 (CH), 116.0 (CH), 114.9
(CH), 67.3 (CH), 55.7 (CH3), 37.6 (CH), 25.3 (CH3); HRMS (ES): m/z:
2848, 1704, 1434, 1383, 1282, 1215, 1130, 1062, 967, 754, 702, 667 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 7.34 7.20 (m, 5H), 4.36 (d, J ˆ 8.8 Hz,
1H), 3.98 (d, J ˆ 7.2 Hz, 1H), 3.08 2.95 (m, 5H), 2.45 (s, 6H), 2.03 1.89
(m, 1H), 1.70 1.60 (m, 1H), 1.25 1.14 (m, 1H), 0.95 0.80 (m, 1H); 13C
(75 MHz, CDCl3, APT): d ˆ 178.6, 178.3 (CO), 142.1 (C), 128.2, 127.5,
126.9, 78.7, 65.2, 51.8, 42.1 [N-N(CH3)2], 40.4 (CH), 25.2 (NCH3), 22.8, 21.7
‡
calcd for C22H23N3O4: 393.1700; found: 393.1704 [M] ; elemental analysis
‡
‡
(CH2); MS (ES): m/z: 340 [M‡Na] , 318 [M‡H] ; HRMS (ES): m/z: calcd
calcd (%) for C22H23N3O4 (393.44): C 67.16, H 5.89, N 10.68; found: C 66.63,
H 5.78, N 10.62.
‡
for C17H23N3O3Na: 340.1637; found: 340.1635 [M‡Na] .
Procedure for the preparation of diene 10: A catalytic amount of glacial
acetic acid (1 drop) followed by SADP (0.60 g, 3.8 mmol, 2 equiv) was
added to a solution of aldehyde 4 (0.35 g, 1.90 mmol, 1 equiv) in anhydrous
Et2O (20 mL). After vigorous stirring for 1 h at reflux, the mixture was
extracted with water (2 Â 10 mL). The organic layer was washed once with
a saturated aqueous solution of sodium chloride, then dried with anhydrous
magnesium sulfate, filtered and concentrated to give the chiral heterodiene
10 as a pale yellowsolid in a 93% crude yield (0.57 g). The crude material
was subjected immediately to the tandem [4‡2]/allylboration reaction.
Spectroscopic data for 5l: m.p. 190 1928C; IR (CHCl3 cast): nÄ ˆ 3497,
2921, 1716, 1597, 1496, 1454, 1384, 1371, 1244, 1141, 971, 829, 792, 692,
622 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.60 7.20 (m, 15H), 6.10 (ddd,
J ˆ 1.5, 3.5, 9.0 Hz, 1H), 5.81 (ddd, J ˆ 2.4, 4.1, 10.6 Hz, 1H), 4.41 (d, J ˆ
8.3 Hz, 1H), 4.20 (d, J ˆ 8.9 Hz, 1H), 3.96 (brs, 1H, OH), 3.71 3.62 (m,
2H), 3.01 (s, 3H); 13C (75 MHz, CDCl3): d ˆ 175.7, 173.6 (CO), 149.3, 139.8,
131.3 (C), 131.0, 129.5, 129.3, 128.9, 128.5, 128.2, 127.1, 126.0, 120.1, 114.4,
‡
76.6, 66.3, 58.6, 39.5 (CH), 35.6 (CH3); MS (ES): m/z: 462 [M‡Na] ;
HRMS (ES): m/z: calcd for C27H25N3O3Na: 462.1794; found: 462.1792
‡
[M‡Na] .
Spectroscopic data for 10: IR (CHCl3 cast): nÄ ˆ 2975, 2933, 2826, 1468,
1213, 924, 667, 647 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.11 (dd, J ˆ 9.1,
17.9 Hz, 1H), 6.93 (d, J ˆ 8.9 Hz, 1H), 5.46 (d, J ˆ 17.9 Hz, 1H), 3.34 3.31
(m, 1H), 3.21 (s, 3H), 2.50 2.20 (m, 2H), 1.91 1.53 (m, 4H), 1.23 (s, 12H),
1.12 (s, 3H), 1.11 (s, 3H); 13C (75 MHz, CDCl3, APT): d ˆ 149.4 (CH), 148.9
(CH), 135.1 (CH), 83.3 (C), 82.3 (C), 76.0 (CH), 48.9 (CH2), 26.7 (CH2),
23.2, 22.1 (CH3), 22.0 (CH3), 21.7 (CH2), 19.4 (CH3); MS (ES): m/z: 323
Spectroscopic data for 5m: IR (CHCl3 cast): nÄ ˆ 3524, 3061, 2937, 1782,
1
1716, 1598, 1494, 1464, 1387, 1371 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ
7.50 7.36 (m, 4H), 7.32 7.18 (m, 7H), 6.94 (dd, J ˆ 7.5, 7.5 Hz, 1H), 6.88
6.82 (m, 1H), 6.80 (d, J ˆ 8.3 Hz, 1H), 6.05 (ddd, J ˆ 1.8, 3.9, 10.5 Hz, 1H),
5.80 (ddd, J ˆ 1.8, 4.5, 10.5 Hz, 1H), 4.80 (dd, J ˆ 2.4, 8.1 Hz, 1H), 4.40 (d,
J ˆ 8.4 Hz, 1H), 3.79 3.71 (m, 1H), 3.66 3.58 (m, 1H), 3.62 (s, 3H), 3.56
(brd, J ˆ 2.7 Hz, 1H), 3.00 (s, 3H); 13C (75 MHz, CDCl3, APT): d ˆ 175.9,
173.9, 156.2, 149.4, 131.6, 131.0, 129.3, 129.2, 128.8, 128.3, 127.3, 126.3, 120.9,
120.6, 119.7, 114.2, 110.4, 68.8, 65.5, 58.8, 55.2, 39.2, 35.5; HRMS (EI): m/z:
‡
[M‡H] ; HRMS (ES): m/z: calcd for C17H32BN2O3: 323.2506; found:
‡
323.2500 [M‡H] .
Spectroscopic data for 11: m.p. 80 828C; IR (CHCl3 cast): nÄ ˆ 3853, 2932,
‡
calcd for C28H27N3O4: 469.2002; found: 469.1998 [M] ; elemental analysis
1715, 1651, 1597, 1499, 1455, 1382, 1179, 1142, 753, 692, 667, 621 cmÀ1
;
calcd (%) for C28H27N3O4 (469.53): C 71.61, H 5.75, N, 8.95; found: C 71.82,
H 5.63, N 8.72.
1H NMR (300 MHz, CDCl3): d ˆ 7.48 7.22 (m, 10H), 6.01 (ddd, J ˆ 1.6, 3.7,
10.6 Hz, 1H), 5.70 (ddd, J ˆ 2.3, 4.5, 10.5 Hz, 1H), 5.38 (s, 1H), 4.80 (d, J ˆ
8.5 Hz, 1H), 4.01 (d, J ˆ 9.6 Hz, 1H), 3.63 3.60 (m, 1H), 3.38 3.28 (m,
2H), 3.36 (s, 3H), 2.92 2.88 (m, 1H), 2.65 2.61 (m, 1H), 1.78 1.71 (m,
1H), 1.68 1.57 (m, 3H), 1.37 (s, 3H), 1.18 (s, 3H); 13C (75 MHz, CDCl3,
APT): d ˆ 175.2, 174.1 (CO), 140.7, 131.7, 130.8, 129.3, 128.8, 128.4, 128.1,
127.2, 126.3, 122.1, 78.5 (C), 76.1, 67.9, 63.2, 60.0, 50.7, 49.1 (CH), 38.4, 25.8,
Spectroscopic data for 5n: m.p. 110 1128C; IR (CHCl3 cast): nÄ ˆ 3021,
2960, 2924, 2852, 1593, 1567, 1496, 1455, 1371, 1259, 1186, 1153, 1100, 1026,
920, 867, 793, 730, 667, 620 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 7.60 7.20
(m, 10H), 6.10 (ddd, J ˆ 2.2, 3.0, 10.4 Hz, 1H), 5.98 (ddd, J ˆ 2.4, 3.5,
10.4 Hz, 1H), 5.82 (d, J ˆ 5.5 Hz, 1H), 5.22 (d, J ˆ 9.3 Hz, 1H), 4.75 4.65
(m, 1H), 3.85 3.75 (m, 1H), 1.92 (s, 3H); 13C (75 MHz, CDCl3, APT): d ˆ
‡
22.7 (CH2), 21.9, 20.6 (CH3); MS (ES): m/z: 475 [M‡H] .
Chem. Eur. J. 2003, 9, No. 2
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0902-0473 $ 20.00+.50/0
473

D. G. Hall et al.
FULL PAPER
Spectroscopic data for 14a (62% crude weight yield): 1H NMR (300 MHz,
(CD3)2CO): d ˆ 10.8 (brs, 1H), 8.12 (d, J ˆ 9 Hz, 2H), 7.55 (d, J ˆ 9 Hz,
2H), 7.60 7.50 (m, 2H), 7.40 7.25 (m, 3H), 6.20 (ddd, J ˆ 11, 4, 1.5 Hz,
1H), 6.02 (ddd, J ˆ 11, 5, 2 Hz, 1H), 5.23 (d, J ˆ 9 Hz, 1H), 4.54 (d, J ˆ
6 Hz, 1H), 4.16 (m, 1H), 4.03 (m, 1H), 2.98 (s, 6H); 13C (75 MHz,
(CD3)2CO, APT): d ˆ 175.0, 174.1, 166.8, 160.1, 142.1, 137.5, 131.0, 130.1,
128.7, 128.5, 128.2, 127.6, 122.9, 75.8, 61.4, 57.3, 43.1 [N-N(CH3)2], 38.7;
[7] N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1998, 120, 11798
11799.
[8] a) J. E. Semple, T. D. Owens, K. Nguyen, O. E. Levy, Org. Lett. 2000,
2, 2769 2772; b) L. Banfi, G. Guanti, R. Riva, Chem. Commun. 2000,
985 986; c) T. D. Owens, E. J. Semple, Org. Lett. 2001, 3, 3301 3304;
d) L. Banfi, G. Guanti, R. Riva, A. Basso, E. Calcagno, Tetrahedron
Lett. 2002, 43, 4067 4069.
[9] For reviews on the synthesis of piperidine-containing natural products,
including indolizidines, see: a) G. Casiraghi, F. Zanardi, G. Rassu, P.
Spanu, Chem. Rev. 1995, 95, 1677 1716; b) J. P. Michael, Nat. Prod.
Rep. 1998, 571 594; c) P. D. Bailey, P. A. Millwood, P. D. Smith,
Chem. Commun. 1998, 633 640; d) A. Mitchinson, A. Nadin, J.
Chem. Soc. Perkin Trans. 1 1999, 2553 2581; e) S. Laschat, T. Dickner,
Synthesis 2000, 1781 1813.
‡
HRMS (ES): m/z: calcd for C23H23N3O: 422.1711; found: 422.1708 [M] .
Spectroscopic data for 14b (54% crude weight yield): 1H NMR (300 MHz,
(CD3)2CO): d ˆ 8.15 (d, J ˆ 9 Hz, 2H), 7.60 7.45 (m, 6H), 6.30 (ddd, J ˆ 11,
4, 2 Hz, 1H), 6.19 (ddd, J ˆ 11, 5, 2 Hz, 1H), 5.23 (dd, J ˆ 9, 1 Hz, 1H), 4.71
(d, J ˆ 4 Hz, 1H), 4.28 (m, 1H), 4.05 (m, 1H), 2.90 (s, 6H); 13C (75 MHz,
(CD3)2CO, APT): d ˆ 173.9, 166.9, 141.7, 137.5, 131.7, 131.2, 131.0, 130.4,
129.2, 127.7, 123.3, 121.9, 74.6, 60.8, 56.8, 43.0 [N-N(CH3)2], 38.0; HRMS
‡
[10] J. Tailor, D. G. Hall, Org. Lett. 2000, 2, 3715 3718.
(ES): m/z: calcd for C23H22N3O5Br: 500.0816; found: 500.0812 [M] .
[11] For reviews, see: a) D. L. Boger in Comprehensive Organic Synthesis,
Vol. 5 (Ed.: L. A. Paquette, Series Eds.: B. M. Trost, I. Fleming),
Pergamon, Elmsford, NY, 1991, pp. 451 512.
Spectroscopic data for 14c (60% crude weight yield): 1H NMR (300 MHz,
(CD3)2CO): d ˆ 8.25 8.10 (m, 2H), 8.02 (m, 1H), 7.80 (d, J ˆ 9 Hz, 1H),
7.70 7.00 (several m, 9H), 6.76 (tt, J ˆ 7, 1, 1H), 6.14 (ddd, J ˆ 10, 4, 1 Hz,
1H), 5.66 (ddd, J ˆ 10, 5, 2 Hz, 1H), 4.73 (dd, J ˆ 9, 1 Hz, 1H), 4.42 (d, J ˆ
9 Hz, 1H), 3.90 (m, 1H), 3.75 (m, 1H); 13C (75 MHz, (CD3)2CO, APT): d ˆ
174.6, 166.8, 148.6, 141.8, 137.3, 131.3, 131.2, 131.1, 129.8, 129.3, 129.0, 128.6,
128.1, 127.5, 120.3, 114.5, 76.4, 68.4, 62.3, 39.1; HRMS (ES): m/z: calcd for
[12] a) M. Vaultier, F. Truchet, B. Carboni, R. W. Hoffmann, I. Denne,
Tetrahedron Lett. 1987, 28, 4169 4172; b) P.-Y. Renard, J.-Y. Lalle-
mand, Bull. Soc. Chim. Fr. 1996, 133, 143 149; c) G. Ohanessian, Y.
Six, J.-Y. Lallemand, Bull. Soc. Chim. Fr. 1996, 133, 1143 1148; d) L.
Garnier, B. Plunian, J. Mortier, M. Vaultier, Tetrahedron Lett. 1996, 37,
6699 6700; e) P.-Y. Renard, J.-Y. Lallemand, Tetrahedron: Asymme-
try 1996, 7, 2523 2524; f) P.-Y. Renard, Y. Six, J.-Y. Lallemand,
Tetrahedron Lett. 1997, 38, 6589 6590; g) R. A. Batey, A. N. Thadani,
A. J. Lough, Chem. Commun. 1999, 475 476; h) Y. Six, J.-Y.
Lallemand, Tetrahedron Lett. 1999, 40, 1295 1296.
‡
C27H23N3O5: 470.1711; found: 470.1701 [M] .
Acknowledgement
Financial support for this research by the Natural Sciences and Engineering
Research Council (NSERC) of Canada (Research and CRD grants), the
University of Alberta, and Shire BioChem Inc. is gratefully acknowledged.
B.B.T. thanks the Canadian Institute of Health Research (CIHR) for a
graduate scholarship. The authors thank Dr. R. MacDonald (Department
of Chemistry, University of Alberta) for the X-ray crystallographic analysis
of compound 7.
[13] For other examples of MCRs involving [4‡2] cycloadditions see: a) K.
Paulvannan, Tetrahedron Lett. 1999, 40, 1851 1854; b) H. Neumann,
A. Jacobi von Wangelin, D. Gˆrdes, A. Spannenberg, M. Beller, J. Am.
¬
Chem. Soc. 2001, 123, 8398 8399; c) P. Janvier, X. Sun, H. Bienayme,
J. Zhu, J. Am. Chem. Soc. 2002, 124, 2560 2567.
[14] Y. Tamura, T. Tsugoshi, Y. Nakajima, Y. Kita, Synthesis 1984, 930
933.
[15] A. Kamabuchi, T. Moriya, N. Miyaura, A. Suzuki, Synth. Comm. 1993,
23, 2851 2859.
[16] R. W. Hoffmann, S. Dresely, Synthesis 1988, 103 106.
[17] See Figures 3 and 4 and accompanying text in: U. Ragnarsson, Chem.
Soc. Rev. 2001, 30, 205 213.
[1] For recent reviews on multicomponent reactions, see: a) R. W.
Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown, T. A. Keating,
Acc. Chem. Res. 1996, 29, 123 131; b) L. Weber, K. Illgen, M.
Almstetter, Synlett 1999, 366 37; c) A. Dˆmling, Comb. Chem. High
Throughput Screening 1999, 1, 1; d) A. Dˆmling, I. Ugi, Angew. Chem.
2000, 112, 3300 3344; Angew. Chem. Int. Ed. 2000, 39, 3168 3210;
[18] CCDC-145481 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB21EZ, UK;
fax: (‡44)1223-336-033; or deposit@ccdc.cam.uk).
[19] a) R. W. Hoffmann, D. Br¸ckner, V. J. Gerusz, Heterocycles 2000, 52,
121 124; b) R. W. Hoffmann, D. Br¸ckner, New J. Chem. 2001, 25,
369 373.
[20] For a reviewon allylboration chemistry, see: D. S. Matteson, Stereo-
directed Synthesis with Organoboranes, Springer, Berlin, 1995, Chap-
ter 7.
[21] R. Beaudegnies, L. Ghosez, Tetrahedron: Asymmetry 1994, 5, 557
560.
¬
e) H. Bienayme, C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 2000,
6, 3321 3329; f) I. Ugi, Pure Appl. Chem. 2001, 73, 187 191.
[2] a) S. L. Schreiber, Science 2000, 287, 1964 1969; b) P. Arya, D. T. H.
Chou, M.-G. Baek, Angew. Chem. 2001, 113, 351 358; Angew. Chem.
Int. Ed. 2001, 40, 339 346.
[3] Dictionary of Alkaloids (Eds.: I. W. Southon, J. Buckingham), Chap-
man and Hall, London, UK, 1989.
[4] A. A. Patchett, R. P. Narglund, Annu. Rep. Med. Chem. 2000, 35,
289 298.
[5] P. A. Grieco, A. Bahsas, Tetrahedron Lett. 1988, 29, 5855 5858.
[6] a) W. Maison, A. L¸tzen, M. Kosten, I. Schlemminger, O. Westerhoff,
J. Martens, J. Chem. Soc. Perkin Trans. 1 1999, 3515; b) W. Maison, A.
L¸tzen, M. Kosten, I. Schlemminger, O. Westerhoff, W. Saak, J.
Martens, J. Chem. Soc. Perkin Trans. 1 2000, 1867 1871; c) E.
[22] The absolute stereochemistry of 11 was assigned tentatively on the
basis of ref. [21].
[23] H. R. Hoveyda, D. G. Hall, Org. Lett. 2001, 3, 3491 3494.
¬
Gonzalez-Zamora, A. Fayol, M. Bois-Choussy, A. Chiaroni, J. Zhu,
Chem. Commun. 2001, 1684 1685.
Received: May 21, 2002 [F4109]
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